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Germline variants of the RUNX1 gene are associated with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (RUNX1-FPDMM), which is characterized by an increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. Patients with FPDMM have also been described to develop B- or T-cell acute lymphoblastic leukemia. We present a pediatric patient with RUNX1-FPDMM that evolved into concurrent MDS and T-cell acute lymphoblastic leukemia after a decade of monitoring with serial blood counts. We aim to highlight the treatment challenges and clinical decision-making that may be anticipated in this unique disorder, as well as the potentially curative role for allogenic hematopoietic stem cell transplant in the first complete remission.

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM., (© 2024. The Author(s).)

Thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) syndrome is an inflammatory disorder with an unclear pathogenesis. We herein report a case of TAFRO syndrome in remission in a patient who experienced recurrent intracranial bleeding despite a normal platelet count and coagulation system. A further investigation suggested the presence of anti-glycoprotein VI (GPVI) autoantibodies in the plasma, which induced platelet dysfunction and bleeding tendency. No new bleeding or relapse of TAFRO syndrome occurred after immunosuppressive therapy was initiated. These findings may help elucidate the autoimmune pathogenesis of TAFRO syndrome.

Excessive bleeding is relatively common in adult inpatients, whether as the primary reason for admission or as a development during the hospital stay. Common causes include structural issues, medication effects, and systemic illnesses; occasionally, unexpected bleeding can develop as a result of an undiagnosed or newly acquired bleeding disorder. The first step in caring for the inpatient who is bleeding is to determine whether the bleeding symptom is truly new or whether the patient has a history of abnormal bleeding. Patients with a history of abnormal bleeding may warrant evaluation for inherited bleeding disorders, such as platelet function disorders, von Willebrand disease, hemophilia, or rare factor deficiencies. Patients with no history of bleeding, for whom other causes, such as liver dysfunction, medication effect, disseminated intravascular coagulation, or certain vitamin deficiencies have been ruled out may require evaluation for acquired coagulopathies, such as acquired hemophilia or acquired von Willebrand disease. Here, we present 3 cases to discuss the diagnosis and management of the 2 most common acquired bleeding disorders as well as a patient with a congenital bleeding disorder with a historical diagnosis., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Germline mutations in RUNX1 can cause a familial platelet disorder that may lead to acute myeloid leukemia, an autosomal dominant disorder characterized by moderate thrombocytopenia, platelet dysfunction, and a high risk of developing acute myeloid leukemia or myelodysplastic syndrome. Discerning the pathogenicity of novel RUNX1 variants is critical for patient management., Objectives: To extend the characterization of RUNX1 variants and evaluate their effects by transcriptome analysis., Methods: Three unrelated patients with long-standing thrombocytopenia carrying heterozygous RUNX1 variants were included: P1, who is a subject with recent development of myelodysplastic syndrome, with c.802 C>T[p.Gln268∗] de novo; P2 with c.586A>G[p.Thr196Ala], a variant that segregates with thrombocytopenia and myeloid neoplasia in the family; and P3 with c.476A>G[p.Asn159Ser], which did not segregate with thrombocytopenia or neoplasia. Baseline platelet evaluations were performed. Ultrapure platelets were prepared for platelet transcriptome analysis., Results: In P1 and P2, but not in P3, transcriptome analysis confirmed aberrant expression of genes recognized as RUNX1 targets. Data allowed grouping patients by distinct gene expression profiles, which were partitioned with clinical parameters. Functional studies and platelet mRNA expression identified alterations in the actin cytoskeleton, downregulation of GFI1B, defective GPVI downstream signaling, and reduction of alpha granule proteins, such as thrombospondin-1, as features likely implicated in thrombocytopenia and platelet dysfunction., Conclusion: Platelet phenotype, familial segregation, and platelet transcriptomics support the pathogenicity of RUNX1 variants p.Gln268∗ and p.Thr196Ala, but not p.Asn159Ser. This study is an additional proof of concept that platelet RNA analysis could be a tool to help classify pathogenic RUNX1 variants and identify novel RUNX1 targets., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical and biological characteristics of familial platelet disorder (FPD) with germline Runt-related transcription factor (RUNX) 1 mutations. Methods: Patients diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with RUNX1 mutations from February 2016 to December 2021 in Wuhan No.1 Hospital underwent pedigree analysis and were screened for gene mutations (somatic and germline). Patients diagnosed with FPD with germline RUNX1 mutations were enrolled and evaluated in terms of clinical characteristics and biological evolution. Bioinformatics analysis was used to assess the pathogenicity of mutations and to analyze the effect of mutated genes on the function of the corresponding protein. Results: Germline RUNX1 mutations were detected in three out of 34 patients suffering from MDS/AML who had RUNX1 mutations. A pedigree of FPD with RUNX1 (RUNX1-FPD) c.562A>C and RUNX1 c.1415T>C mutations was diagnosed, and the mutations were of patrilineal origin. Bioinformatics analysis indicated that the locus at positions 188 and 472 in the AML-1G type of RUNX1 was highly conserved across different species, and that variations might influence functions of the proteins. The mutations were evaluated to be highly pathogenic. Of the nine cases with germline RUNX1 mutations: two patients died due AML progression; one case with AML survived without leukemia after transplantation of hemopoietic stem cells; four patients showed mild-to-moderate thrombocytopenia; two cases had no thrombocytopenia. During the disease course of the proband and her son, mutations in RUNX1, NRAS and/or CEBPA and KIT appeared in succession, and expression of cluster of differentiation-7 on tumor cells was enhanced gradually. None of the gene mutations correlated with the tumor were detected in the four cases not suffering from MDS/AML, and they survived until the end of follow-up. Conclusions: RUNX1-FPD was rare. The mutations c.562A>C and c.1415T>C of RUNX1 could be the disease-causing genes for the family with RUNX1-FPD, and these mutations could promote malignant transformation. Biological monitoring should be carried out regularly to aid early intervention for family members with RUNX1-FPD.

Introduction: The National Hemophilia Foundation State of the Science Research Summit initiative sought to unify research efforts in the US inherited bleeding disorders (BDs) community around key topics of importance to people living with inherited BDs, the lived experience experts., Areas Covered: This community-led and -informed project focused on six broad areas - hemophilia A or B; von Willebrand Disease (VWD), platelet dysfunctions and other mucocutaneous inherited BDs; ultra-rare inherited BDs; the unique challenges of people with the potential to menstruate with inherited BDs; diversity, equity and inclusion, health services research, and implementation science; and facilitating research in the inherited BD community through designing an optimizied research infrastructure, enabling resources and funding, and furthering workforce capabilities required to execute the research priorities., Expert Opinion: The work summarized here, and in the accompanying supplement manuscripts , has implications not only for the US population but for people globally who have inherited BDs. The information is equally relevant to people living with hemophilia, VWD, the spectrum of inherited platelet disorders, ultra-rare factor deficiencies, and all other inherited BDs as it is to the health care providers and researchers focused on the care and treatment of inherited BDs in the US and globally.

Reproductive tract bleeding is an underappreciated health care problem among adolescent and young adult (AYA) females with inherited bleeding disorders (IBDs) comprising von Willebrand disease, platelet disorders, hemophilia carriership, and rare factor deficiencies. IBDs are prevalent in women of all ages and have been detected in about 50% of women with menorrhagia or heavy menstrual bleeding (HMB) and about 20% of women with postpartum hemorrhage (PPH). The clinical spectrum of gynecologic and obstetric bleeding in AYA with IBDs ranges from HMB, ovulation bleeding, and surgical bleeding to miscarriages and life-threatening PPH. Reproductive tract bleeding adversely affects the quality of life of this patient population, in addition to causing substantial morbidity and mortality. Early diagnosis of IBDs offers the opportunity for timely intervention with hormones, hemostatic agents, and prophylaxis with factor concentrates, thereby improving outcomes. This review summarizes the epidemiology, pathophysiology, clinical manifestations, diagnostic approach, management, and prophylaxis for reproductive tract bleeding in AYA with IBDs. This review provides a multidisciplinary approach to the problem, which is critical to improve the outcomes of this patient population., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2022 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Germline pathogenic variants in RUNX1 are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in RUNX1 accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline RUNX1 intragenic deletions. The aforementioned deletions encompass exons 1-2 and 9-10 respectively, with the exon 9-10 deletion being previously unreported. RNA sequencing of patients carrying the exon 9-10 deletion revealed a fusion with LINC00160 resulting in a change in the 3' sequence of RUNX1 . Expression analysis of the transcript isoform demonstrated altered RUNX1a/b/c ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic RUNX1 deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition.

Inherited platelet disorders are important conditions that often manifest with bleeding. These disorders have heterogeneous underlying pathologies. Some are syndromic disorders with non-blood phenotypic features, and others are associated with an increased predisposition to developing myelodysplasia and leukemia. Platelet disorders can present with thrombocytopenia, defects in platelet function, or both. As the underlying pathogenesis of inherited thrombocytopenias and platelet function disorders are quite diverse, their evaluation requires a thorough clinical assessment and specialized diagnostic tests, that often challenge diagnostic laboratories. At present, many of the commonly encountered, non-syndromic platelet disorders do not have a defined molecular cause. Nonetheless, significant progress has been made over the past few decades to improve the diagnostic evaluation of inherited platelet disorders, from the assessment of the bleeding history to improved standardization of light transmission aggregometry, which remains a "gold standard" test of platelet function. Some platelet disorder test findings are highly predictive of a bleeding disorder and some show association to symptoms of prolonged bleeding, surgical bleeding, and wound healing problems. Multiple assays can be required to diagnose common and rare platelet disorders, each requiring control of preanalytical, analytical, and post-analytical variables. The laboratory investigations of platelet disorders include evaluations of platelet counts, size, and morphology by light microscopy; assessments for aggregation defects; tests for dense granule deficiency; analyses of granule constituents and their release; platelet protein analysis by immunofluorescent staining or flow cytometry; tests of platelet procoagulant function; evaluations of platelet ultrastructure; high-throughput sequencing and other molecular diagnostic tests. The focus of this article is to review current methods for the diagnostic assessment of platelet function, with a focus on contemporary, best diagnostic laboratory practices, and relationships between clinical and laboratory findings.

Introduction: Frequent and severe bleeding events (SBE) in patients with inherited qualitative platelet disorders Bernard-Soulier Syndrome (BSS) and Glanzmann Thrombasthenia (GT) can lead to secondary iron deficiency anemia (IDA). SBE are primarily treated with platelet transfusions or recombinant activated factor VII (rFVIIa) infusions. The impact of IDA on bleeding management and disease outcomes is understudied., Aim: To evaluate bleeding management, outcomes, and any association with IDA in pediatric patients with BSS and GT., Methods: Retrospective chart-review of pediatric patients with BSS or GT followed at a single hemophilia treatment center between 2007 and 2019., Results: We identified 14 patients with BSS (n = 2) or GT (n = 12). Patients received rFVIIa (7%), platelet transfusions (7%), or a combination of both (57%) for SBE. Eleven patients (79%) had IDA requiring oral and/or intravenous iron replacement and 50% required red blood cell transfusions. Due to recurrent SBE and refractory IDA, three patients (21%) received rFVIIa prophylaxis at 90 μg/kilogram 2-3 times/week for ≥15 months. Patients initiated on rFVIIa prophylaxis had a median baseline hemoglobin of 9.8 g/dL (min-max: 8.0-10.7 g/dL) compared to 11.7 g/dL (8.4-13.8 g/dL) for patients treated on-demand. Following initiation of rFVIIa prophylaxis, median hemoglobin and ferritin increased by 1.3 g/dL (0.7-2.5 g/dL) and 14.6 ng/mL (0.2-42.9 ng/mL), respectively, and bleeding rates were reduced by 7-78%., Conclusion: IDA is a known complication of recurrent bleeding events in individuals with inherited bleeding disorders. Routine monitoring for IDA may help improve bleeding management and reduce bleed burden in BSS/GT., (© 2022 John Wiley & Sons Ltd.)

Objectives: Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data., Methods: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface-activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients., Results: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels ( r  = 0.17, p -value = 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (-2 standard deviation of reference range) was found in 79 (53%, 95% confidence interval [CI]: 44-61%) patients, of whom 10 (6.7%, 95% CI: 3.3-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (odds ratio [OR]: 1.05, 95% CI: 1.01-1.1) and low P-selectin reactivity (OR: 2.03, 95% CI: 1.25-3.35) were associated with more than one bleeding manifestation., Conclusion: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation., Competing Interests: S.R.-V.: honoraria and research funding from Takeda, Pfizer, Sanofi/Genzyme. M.N., D.F., T.D., M.I., M.B.-C.: no conflict of interest to declare. A.D.M.: honoraria: AstraZeneca, Stasys. Research funding: argenx. A.L.F.: research funding: argenx, AstraZeneca, BeiGene, Pfizer, Surface Oncology, Sysmex. A.Z.: honoraria: Takeda, Pfizer, and BioEvents. Consultancy fees: Takeda, AvroBio, Insightec, and Prevail Therapeutics., (Thieme. All rights reserved.)

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity., Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found., Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry., Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining., Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Congenital platelet disorders (CPDs) are rare bleeding disorders that are associated with mucocutaneous bleeds. However, data on vaginal bleeding in women with CPDs are scarce. A set of generic and bleeding-specific questionnaires were used to evaluate the prevalence of vaginal bleeding, its impact on quality of life (QoL) and sexual functioning and the consequences for pregnancy, miscarriage and delivery in a cohort of women who were referred for diagnostic evaluation for CPDs. A total of 78 women included in the study were either diagnosed with a CPD (n = 35) or were clinically suspected of a CPD (n = 43). Heavy menstrual bleeding (HMB) was reported by a large proportion of women, which mainly started at menarche. In all, 76% of women received any kind of HMB treatment, often leading to surgical prodecures. HMB was shown to have a high impact on QoL, which improved upon treatment. Even though women reported that vaginal bleeding affects sexuality, this topic is not frequently discussed with physicians. Heavy blood loss frequently occurred after miscarriage/delivery, often requiring treatment. Women with (suspected) CPDs frequently encounter HMB, negatively impacting daily life and sexual functioning. Together with peripartum bleeding, these data highlight the burden of vaginal bleeding in CPDs and importance of adequate treatment., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Platelet-transfusion refractoriness (PTR) is common in patients with hematological malignancies. The etiology of immune PTR is typically human leukocyte antigen (HLA) antibodies (Abs) from pregnancy or previous transfusion. Herein, we report PTR in the setting of induction chemotherapy for acute myelogenous leukemia (AML) from Abs against CD36/glycoprotein (GP)IV. A 66-year-old African American woman presented with anemia and thrombocytopenia. She was found to have transfusion-dependent AML, and a 7 + 3 regimen (7 days of standard-dose cytarabine and 3 days of an anthracycline antibiotic or an anthracenedione, most often daunorubicin) was initiated. The patient developed profound thrombocytopenia, with platelet nadir of 0 by day 13. The results of HLA antibody screening were negative. However, the results of a screening test for platelet-specific antibodies screen showed Abs against cluster of differentiation (CD)36. The platelets of the patient lacked expression of CD36, and DNA analysis showed mutations in the CD36 gene. HLA Ab-mediated PTR is common in patients with hematological malignancies. However, once HLA Abs are excluded, other less-frequent Abs should be considered, particularly in patient populations of Asian, African, or Middle Eastern descent., (© American Society for Clinical Pathology 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objective: Gastrointestinal (GI) polyps with unknown malignant potential and a platelet storage pool deficiency that increases the risk of severe intraoperative and other types of bleeding have been identified in McCune-Albright syndrome (MAS). The natural course of these disorders has not been well characterized. The aim of this study was to report the follow-up of GI polyps and platelet dysfunction (PD) in a cohort of 28 patients with MAS., Methods: Twenty-eight patients with MAS (15 females) were included. Endoscopic screening for GI polyps was undertaken in 14 subjects and 19 were tested for PD., Results: Six subjects (5 males) were diagnosed with GI polyps at a median age of 23 (range 15-43) years, and were monitored for a median period of 8 (range 4.5-11.5) years. At endoscopic follow-up, the 4 patients with hamartomatous polyps at first endoscopy had either normal findings (n = 2), or duodenal gastric metaplasia (n = 2). Two patients with caecal polyps were identified. Of 8 subjects with a platelet storage pool deficiency, 5 required transfusions during surgery, and subsequent platelet cover in 2 markedly reduced intraoperative blood loss., Conclusions: New polyps with uncertain malignant potential are diagnosed after long term follow-up in MAS. Platelet cover reduces the need for red blood cell transfusion during orthopaedic surgery and may be useful to reduce non-operative bleeding events. We recommend regular upper and lower endoscopy and screening for PD in all MAS patients., (© 2020 S. Karger AG, Basel.)

Background: Intrauterine balloon tamponade is commonly used to treat postpartum hemorrhage refractory to pharmacologic interventions. It has not been well-studied in girls or adolescents for treatment of acute heavy menstrual bleeding., Case: A 10-year old girl presented with heavy menstrual bleeding that did not respond to medical management. Placement of a Foley catheter for intrauterine tamponade was used to control bleeding. She was subsequently diagnosed with a platelet function disorder., Conclusion: Foley catheter placement is a low-risk, low-cost, and readily accessible option for intrauterine tamponade to consider for young girls and adolescents with acute heavy menstrual bleeding resistant to medical management.

Stormorken syndrome is a rare genetic disorder (MIM 185070) first reported in 1983 with thrombocytopenia, muscle weakness, asplenia, and miosis caused by a mutation of the stromal interaction molecule 1 ( STIM1) gene. 1 The muscle weakness is caused by a myopathy with tubular aggregate formation. We report a family in which both child and mother presented with proximal muscle weakness and thrombocytopenia. Histologic, histochemical, and electron microscopy studies were performed on the muscle specimen. It documented accumulation of tubular aggregates and chronic myopathic changes with dystrophic features. Genetic testing revealed that both mother and son carried a missense mutation of c.326A>G in exon 3 of the STIM1 gene, which is novel for Stormorken syndrome. We suggest that patients with unexplained chronic idiopathic thrombocytopenia and proximal weakness have genetic testing for Stormorken syndrome.

Introduction: Even though thrombotic events are rare in patients with coagulation deficiencies, several cases of both arterial and venous thromboses have been reported in patients with single coagulation factor defects and platelet defects. Thromboses have been described both in hemophilia A and B, von Willebrand disease as well as in many other rare congenital coagulation factor and platelet defects. Thromboses may also occur in patients with acquired hemophilia and in patients with severe thrombocytopenia due to hematological malignancies or intensive chemotherapy. Areas covered: We searched in the PubMed database to identify scientific publications describing patients with bleeding disorders and thromboses and published suggestions/guidelines for the treatment of thromboses in such patients. Expert commentary: The article gives a review of published case reports/studies of thromboses in these patients. Thromboses are rare in all these diseases. There is generally a lack controlled clinical studies for the use of anticoagulation therapy in such patients, and the article gives an overview of published suggestions and expert opinions based on the experience at large centers for treatment of thromboses in patients with congenital coagulation defects, acquired hemophilia and severe thrombocytopenia.

There is a complex and not fully elucidated association between pulmonary arterial hypertension (PAH) and coagulation disorders. The goal of this study was to evaluate platelet function, coagulation and fibrinolysis in PAH patients at diagnosis, before PAH-specific treatment initiation. We enrolled 20 healthy controls and 30 PAH patients (20 with connective tissue disease (CTD-PAH) and 10 idiopathic (iPAH)). None of the participants was on any antiplatelet or anticoagulation therapy. Blood samples from PAH patients were collected during the initial right heart catheterization. All subjects were assessed with platelet function analyzer-100 (PFA-100), epinephrine (Epi) and ADP-induced light transmission aggregometry (LTA), thromboelastometry (ROTEM) and endogenous thrombin potential (ETP). Our results showed that Epi and ADP-LTA values were significantly lower in newly diagnosed PAH patients compared to controls. Disaggregation was present in 73% of patients, a characteristic not seen in healthy individuals. In ROTEM assay, CT and CFT measurements were significantly higher and a angle lower compared to controls. ETP testing revealed significantly reduced outcomes in AUC, Cmax and Tmax. When CTD-PAH and iPAH patient groups were compared, iPAH ADP-LTA values were significantly decreased compared to CTD-PAH. In conclusion, newly diagnosed PAH patients presented with decreased platelet aggregation, clot propagation and thrombin generation, along with delayed initiation of the coagulation process. These hemostatic deficits could indicate an "exhaustion" of the coagulation process that could be caused by endothelial dysfunction and chronic activation of the procoagulant pathways. Further studies are warranted to confirm these laboratory findings and assess their potential clinical significance.

The pathophysiology of impaired platelet function in acquired disorders is often poorly understood. We report two unrelated patients with hematologic malignancies associated with acquired severe bleeding diathesis, and complex platelet function abnormalities, including overproduction of the physiological inhibitor cyclic-AMP (cAMP). Patient 1, with mild macrocytic anemia and thrombocytopenia (100 x 10 9 /L), was diagnosed with chronic myelomonocytic leukemia a few months after the onset of her bleeding diathesis and our analysis of platelet function. Patient 2, with bleeding diathesis of recent onset, was studied when his myelodysplastic syndrome with excess blasts had already progressed to acute myeloid leukemia. In both patients, platelet aggregation/ATP secretion, serum thromboxane B 2 , intraplatelet content of ADP, ATP, serotonin, and fibrinogen were severely impaired. Baseline platelet cAMP levels were mildly elevated and markedly increased after stimulation by prostaglandin E 1 . In conclusion, these are the first patients with myeloid malignancies associated with acquired severe platelet dysfunction and overproduction of cAMP.

Objectives: The bipolar affective disorder (BAD) pathophysiology is multifactorial and has not been fully clarified., Method: We measured selected mitochondrial parameters in peripheral blood components. The analyses were performed for patients suffering from a manic episode during remission and were compared to those performed for healthy controls. BAD was clinically evaluated using well-established diagnostic scales and questionnaires. Mitochondrial respiration was examined in intact and permeabilized blood platelets using high-resolution respirometry. The citrate synthase (CS) and electron transport system (ETS) complex (complex I, II, and IV) activities were examined in platelets., Results: The CS, complex II and complex IV activities were decreased in the BAD patients, complex I activity was increased, and the ratio of complex I to CS was significantly increased. In the intact platelets, respiration after complex I inhibition and residual oxygen consumption were decreased in the BAD patients compared to the healthy controls. In the permeabilized platelets, a decreased ETS capacity was found in the BAD patients. No significant differences were found between BAD patients in mania and remission., Conclusion: Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. We conclude that complex I and its abnormal activity contribute to defects in cellular energy metabolism during a manic episode and that the deficiency in the complex's functioning, but not the availability of oxidative phosphorylation substrates, seems to be responsible for the decreased ETS capacity in BAD patients. The observed parameters can be further evaluated as 'trait' markers of BAD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Inherited platelet disorders are rare bleeding syndromes due to either platelet function abnormalities or thrombocytopenia which may be associated with functional defects. The haemorrhagic symptoms observed in these patients are mostly muco-cutaneous and of highly variable severity. Although 30 to 50% of the platelet disorders are still of unknown origin, the precise diagnosis of these pathologies by specialized laboratories together with haemorrhagic scores enables an assessment of the risk of bleeding in each patient. Depending on the diagnostic elements collected, an appropriate medical procedure can be proposed for each situation: scheduled or emergency surgical interventions and pregnancy follow-up. The pathologies most at risk correspond to Glanzmann's thrombasthenia, Bernard-Soulier syndrome, severe thrombocytopenia (<40,000 platelets/μL) and signalling protein abnormalities affecting the activation of GPIIb-IIIa, a membrane glycoprotein essential for platelet aggregation. For these particular patients, in whom the risk of bleeding can be increased by a factor of 40, management protocols during surgical procedures are generally based on the use of conventional platelet concentrates, for both prophylaxis and the control of active bleeding. The perinatal period in women with platelet disorders and their new-born also require special attention. Indeed, beyond unpredictable delivery haemorrhages, bleeding requiring a blood transfusion is observed after delivery in more than 50% of women with Glanzmann's thrombastenia or Bernard-Soulier syndrome., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: CD36 deficiency is characterized by limited cellular long chain fatty acid uptake in the skeletal and cardiac muscles and often causes energy crisis in these muscles. However, suitable treatment for CD36 deficiency remains to be established. The aim of this study was to evaluate the clinical and metabolic effects of medium chain triacylglycerols (MCTs) in two CD36-deficient preschool children who often developed fasting hypoglycemia and exercise-induced myalgia., Methods: Fasting blood glucose, total ketone bodies, and free fatty acids were examined and compared for usual supper diets and for diets with replacement of one component with 2 g/kg of 9% MCT-containing milk (MCT milk). Changes in serum creatine kinase and alanine aminotransferase levels, resulting from replacement of glucose water intake with 1 g/kg of MCT milk and determined by using bicycle pedaling tasks, were examined and compared. Hypoglycemic and/or myalgia episodes in daily life were also investigated., Results: Biochemically, participants' blood glucose and total ketone bodies levels after overnight fasting substantially increased after dietary suppers containing MCT milk. Increases in serum creatine kinase and alanine aminotransferase levels resulting from the bicycle pedaling task were suppressed by MCT milk. Hypoglycemia leading to unconsciousness and tachycardia before breakfast decreased after introduction of dietary suppers containing MCT milk. Occurrence of myalgia in the lower limbs also decreased after intakes of MCT milk before long and/or strenuous exercising., Conclusion: Our results suggest that MCTs can prevent fasting hypoglycemia and exercise-induced myalgia in CD36-deficient young children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Chronic heart failure (HF) is a major emerging healthcare problem, associated with a high morbidity and mortality. Left ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage HF. Despite its great benefit, the use of LVAD is associated with a high risk of complications. Bleeding, pump thrombosis and thromboembolic events are frequently observed complications, with bleeding complications occurring in over a third of the patients. Although the design of the third-generation LVAD has improved greatly, these hemostatic complications still occur. The introduction of an LVAD into the circulatory system results in an altered hematological balance as a consequence of blood-pump interactions, changes in hemodynamics, the rheology, and the concomitant need for anticoagulation while implanted with an LVAD. The majority, if not all, LVAD patients experience a form of platelet dysfunction and impaired von Willebrand factor activity, leading to acquired coagulopathy disorders. Different diagnostic tools and treatment strategies have been reported; however, they require validation in LVAD patients. The present review focuses on acquired coagulopathies, describing the incidence, impact and underlying mechanism of acquired coagulopathy disorders in patients supported by LVADs. In addition, we will discuss diagnostic and management strategies for these acquired coagulopathies., (© 2017 International Society on Thrombosis and Haemostasis.)

Objective: To use standardized bleeding questionnaires to compare the severity and patterns of epistaxis in children with a mucocutaneous bleeding disorder and control children., Study Design: The epistaxis sections of the Pediatric Bleeding Questionnaire (PBQ) administered to pediatric patients with von Willebrand disease or a platelet function disorder and healthy control children were reviewed. Scores and features of epistaxis (frequency, duration, onset, site, seasonal correlation, and need for medical/surgical intervention) were recorded. A PBQ epistaxis score ≥2 was defined as clinically significant. The Katsanis epistaxis scoring system was administered to eligible patients, ie, with ≥5 episodes of epistaxis per year., Results: PBQ epistaxis scores were obtained for 66 patients, median age 12 years (range 0.6-18.3 years), and 56 control children. The median PBQ epistaxis score in patients was 2 vs 0 in control children (P <.0001). All of the features of epistaxis, except spontaneous onset, occurred in a significantly greater proportion of patients than control children with epistaxis. A total of 50% of the patients were graded as having severe epistaxis by the Katsanis epistaxis scoring system, and 30 of these (91%) had a clinically significant PBQ epistaxis score., Conclusion: Standardized bleeding questionnaires are useful in the assessment of epistaxis severity and pattern and may help to distinguish children with and without a mucocutaneous bleeding disorder., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Congenital platelet function disorders are often the result of defects in critical signal transduction pathways required for platelet adhesion and clot formation. Mutations affecting RASGRP2, the gene encoding the Rap GTPase activator, CalDAG-GEFI, give rise to a novel, and rare, group of platelet signal transduction abnormalities. We here report platelet function studies for two brothers (P1 and P2) expressing a novel variant of RASGRP2, CalDAG-GEFI(p.Gly305Asp). P1 and P2 have a lifelong history of bleeding with severe epistaxis successfully treated with platelet transfusions or rFVIIa. Other bleedings include extended hemorrhage from minor wounds. Platelet counts and plasma coagulation were normal, as was αIIbβ3 and GPIb expression on the platelet surface. Aggregation of patients' platelets was significantly impaired in response to select agonists including ADP, epinephrine, collagen, and calcium ionophore A23187. Integrin αIIbβ3 activation and granule release were also impaired. CalDAG-GEFI protein expression was markedly reduced but not absent. Homology modeling places the Gly305Asp substitution at the GEF-Rap1 interface, suggesting that the mutant protein has very limited catalytic activity. In summary, we here describe a novel mutation in RASGRP2 that affects both expression and function of CalDAG-GEFI and that causes impaired platelet adhesive function and significant bleeding in humans.

Objective: The extent that inherited bleeding disorders affect; number, size and location of bruises in young children <6 years., Design: Prospective, longitudinal, observational study., Setting: Community., Patients: 105 children with bleeding disorders, were compared with 328 without a bleeding disorder and classified by mobility: premobile (non-rolling/rolling over/sitting), early mobile (crawling/cruising) and walking and by disease severity: severe bleeding disorder factor VIII/IX/XI <1 IU/dL or type 3 von Willebrand disease., Interventions: Number, size and location of bruises recorded in each child weekly for up to 12 weeks., Outcomes: The interventions were compared between children with severe and mild/moderate bleeding disorders and those without bleeding disorders. Multiple collections for individual children were analysed by multilevel modelling., Results: Children with bleeding disorders had more and larger bruises, especially when premobile. Compared with premobile children without a bleeding disorder; the modelled ratio of means (95% CI) for number of bruises/collection was 31.82 (8.39 to 65.42) for severe bleeding disorders and 5.15 (1.23 to 11.17) for mild/moderate, and was 1.81 (1.13 to 2.23) for size of bruises. Children with bleeding disorders rarely had bruises on the ears, neck, cheeks, eyes or genitalia., Conclusions: Children with bleeding disorder have more and larger bruises at all developmental stages. The differences were greatest in premobile children. In this age group for children with unexplained bruising, it is essential that coagulation studies are done early to avoid the erroneous diagnosis of physical abuse when the child actually has a serious bleeding disorder, however a blood test compatible with a mild/moderate bleeding disorder cannot be assumed to be the cause of bruising., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

A subset of patients with familial platelet disorder with propensity to myeloid malignancy and germline RUNX1 mutation develops hematological malignancies, often myelodysplastic syndrome/acute myeloid leukemia, currently recognized in the 2016 WHO classification. Patients who develop hematologic malignancies are typically young, respond poorly to conventional therapy, and need allogeneic stem cell transplant from non-familial donors. Understanding the spectrum of bone marrow morphologic and genetic findings in these patients is critical to ensure diagnostic accuracy and develop criteria to recognize the onset of hematologic malignancies, particularly myelodysplastic syndrome. However, bone marrow features remain poorly characterized. To address this knowledge gap, we analyzed the clinicopathologic and genetic findings of 11 patients from 7 pedigrees. Of these, 6 patients did not develop hematologic malignancies over a 22-month follow-up period; 5 patients developed hematologic malignancies (3 acute myeloid leukemia; 2 myelodysplastic syndrome). All patients had thrombocytopenia at initial presentation. All 6 patients who did not develop hematologic malignancies showed baseline bone marrow abnormalities: low-for-age cellularity (n=4), dysmegakaryopoiesis (n=5), megakaryocytic hypoplasia/hyperplasia (n=5), and eosinophilia (n=4). Two patients had multiple immunophenotypic alterations in CD34-positive myeloblasts; 1 patient had clonal hematopoiesis. In contrast, patients who developed hematologic malignancies had additional cytopenia(s) (n=4), abnormal platelet granulation (n=5), bone marrow hypercellularity (n=4), dysplasia in ≥2 lineages including megakaryocytes (n=3) and acquired clonal genetic aberrations (n=5). In conclusion, our study demonstrated that specific bone marrow abnormalities and acquired genetic alterations may be harbingers of progression to hematological malignancies in patients with familial platelet disorder with germline RUNX1 mutation., (Copyright© 2017 Ferrata Storti Foundation.)

Invasive procedures in children are in most cases elective and are carried out in otherwise healthy children. While many surgeries are still performed in a hospital, more and more procedures are defined as "outpatient procedures," leading to increased discussion about safety and risks. This review will examine common practices, review the sparse literature and provide recommendations regarding the identification of children with increased bleeding risk, planning for children with known bleeding disorders and strategies for perioperative management. In conclusion, after careful planning, surgeries can be performed safely even in children with known bleeding disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Inherited platelet deficiency and/or dysfunction may be more common in the general population than has previously been appreciated. In 2013 the Israeli Inherited Platelet Disorder (IPD) Registry was established., Methods: Clinical and laboratory data were collected to pre-specified registration forms. The study protocol was approved by the local hospital ethics committees., Results: To date we have included in the registry 89 patients (male 52%) from 79 families. Most patients (74%) have a not-yet specified inherited thrombocytopenia (n=39) or non-specific platelet function disorder (n=27). Full clinical data were available for 81 (91%) patients. The median (range) age at presentation and time of follow-up were 1.8years (1day-17.8years) and 4.7 (0-26) years, respectively. The Pediatric Bleeding Questionnaire was available for 78patients; abnormal bleeding score (≥2) was recorded in 47 (52.8%, 95% CI 42%-63.5%) patients and was less frequent in patients followed for isolated thrombocytopenia. Abnormal score was associated with a longer time of follow-up, OR 1.19 (95% CI 1.04-1.36)., Conclusion: Long term follow-up of patients with IPDs is important as bleeding risks may increase with time. We expect that clinical and laboratory information of patients/families with IPDs gathered in a systemic format will allow for better diagnosis and treatment of these patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence., (Copyright© 2017 Ferrata Storti Foundation.)

Familial platelet disorder with predisposition to acute myeloid leukaemia (FPD/AML) is characterized by germline RUNX1 mutations, thrombocytopaenia, platelet dysfunction and a risk of developing acute myeloid and in rare cases lymphoid T leukaemia. Here, we focus on a case of a man with a familial history of RUNX1 R174Q mutation who developed at the age of 42 years a T2-ALL and, 2 years after remission, an AML-M0. Both AML-M0 and T2-ALL blast populations demonstrated a loss of 1p36.32-23 and 17q11.2 regions as well as other small deletions, clonal rearrangements of both TCRγ and TCRδ and a presence of 18 variants at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone, which gave rise to subclonal populations. Next generation sequencing (NGS) performed on peripheral blood-derived CD34 + cells 5 years prior to T2-ALL development revealed only the missense TET2 P1962T mutation at a frequency of 1%, which increases to more than 40% in fully transformed leukaemic T2-ALL and AML-M0 clones. This result suggests that TET2 P1962T mutation in association with germline RUNX1 R174Q mutation leads to amplification of a haematopoietic clone susceptible to acquire other transforming alterations., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Introduction: Inherited defects in RUNX1 are important causes of platelet function disorders., Aim: Our goals were to evaluate RUNX1-related platelet disorders among individuals evaluated for uncharacterized, inherited platelet function disorders and test a proof of concept that bleeding risks could be quantitatively estimated for typical families with an inherited platelet function disorder., Methods: Index cases with an uncharacterized inherited platelet function disorder were subjected to exome sequencing with confirmation of RUNX1 mutations by Sanger sequencing. Laboratory findings were obtained from medical records and persistence of platelet non-muscle myosin heavy chain IIB (MYH10), a biomarker of RUNX1 defects, was assessed by Western blotting. Bleeding histories were assessed using standardized assessment tools. Bleeding risks were estimated as odds ratios (OR) using questionnaire data for affected individuals compared to controls., Results: Among 12 index cases who had their exomes sequenced, one individual from a family with eight study participants had a c.583dup in RUNX1 that segregated with the disease and was predicted to cause a frameshift and RUNX1 haploinsufficiency. Unlike unaffected family members (n = 2), affected family members (n = 6) had increased bleeding scores and abnormal platelet aggregation and dense granule release responses to agonists but only some had thrombocytopenia and/or dense granule deficiency. This family's mutation was associated with persistence of MYH10 in platelets and increased risks (OR 11-440) for wound healing problems and mild bleeding symptoms, including bleeding interfering with lifestyle in women., Conclusion: Inherited platelet dysfunction due to a RUNX1 haploinsufficiency mutation significantly increases bleeding risks., (© 2017 John Wiley & Sons Ltd.)

Rationale: Ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia (EDTA-PTCP) is a rare phenomenon characterized by spuriously low platelet counts when EDTA reacts with harvested blood. However, to the best of our knowledge, only two cases involving EDTA-PTCP in postoperative patients with sepsis have been reported. Here, we describe a case of EDTA-PTCP that appeared transiently in a postoperative patient with sepsis., Patient Concerns: A 68-year-old female patient underwent laparoscopic tension-free hernioplasty for incisional hernia. Postoperatively, the patient developed very low platelet counts. The number of platelets in this patient had not improved following treatment with fresh-frozen plasma and platelet transfusions., Diagnoses: The diagnosis of EDTA-PTCP was confirmed from the discovery of platelet aggregation in peripheral blood smears., Interventions: We used sodium citrate-anticoagulated blood samples for platelet counting., Outcomes: The patient's platelet counts returned to normal with the use of sodium citrate-anticoagulated blood samples. Furthermore, the phenomenon of EDTA-PTCP disappeared when the patient was cured., Lessons: The phenomenon of low platelet counts in postoperative patients with sepsis should be considered as possible EDTA-PTCP. In addition, peripheral blood smears and the use of sodium citrate anticoagulant are effective and valuable methods that can help identify EDTA-PTCP.

Platelet defects due to hyper-responsive GPIbα causing enhanced VWF interaction, counter-intuitively result in bleeding rather than thrombosis. The historical explanation of platelet/VWF clearance fails to explain mechanisms of impaired haemostasis particularly in light of reported poor platelet binding to fibrinogen. This study aimed to evaluate the defects of platelets with hyper-responsive GPIbα and their contribution to impaired in vivo thrombosis. Using the PT-VWD mouse model, platelets from the hTg G233V were compared to control hTg WT mice. Platelets' pro-coagulant capacity was evaluated using flowcytometry assessment of P-selectin and annexin V. Whole blood platelet aggregation in response to ADP, collagen and thrombin was tested. Clot kinetics using laser injury thrombosis model and the effect of GPIbα inhibition in vivo using 6B4; a monoclonal antibody, were evaluated. Thrombin-induced platelet P-selectin and PS exposure were significantly reduced in hTg G233V compared to hTg WT and not significantly different when compared to unstimulated platelets. The hTg G233V platelets aggregated normally in response to collagen, and had a delayed response to ADP and thrombin, when compared to hTg WT platelets. Laser injury showed significant impairment of in vivo thrombus formation in hTg G233V compared to hTg WT mice. There was a significant lag in in vitro clot formation in turbidity assay but no impairment in thrombin generation was observed using thromboelastography. The in vivo inhibition of GPIbα facilitated new - unstable - clot formation but did not improve the lag. We conclude platelets with hyper-responsive GPIbα have complex intrinsic defects beyond the previously described mechanisms. Abnormal signalling through GPIbα and potential therapy using inhibitors require further investigations.

Hemostatic disorders are typically associated with prolonged bleeding after or during surgical procedures. The aim of the study was to increase the efficiency of oral surgery in these patients using erbium laser. Selected 46 patients receiving oral surgery were randomly divided in 2 groups: 43 patients with thrombocytopenia, trombocytemia and other platelet disorders treated with erbium laser and a control group of 43 patients without concomitant pathology determined for conventional surgical treatment. No postoperative bleeding was seen in group 1. Conventional procedures were associated with significantly more postoperative pain and epithelization took 1-3 days longer. Erbium laser radiation is an up-to-date method which can be successfully used for oral surgery in patients with hemostatic disorders.

Introduction: The determination of an underlying genetic predisposition is not automatically part of the diagnosis of hematological malignancies (HM) in routine practice. However, it is assumed that genetic predispositions to HM are currently underestimated due to great variations in disease phenotype, variable latency and incomplete penetrance. Most of patients do not display any biological or clinical signs besides the overt hematological disease and many of them have a lack of personal or family history of malignancies. Areas covered: Collaborative studies and important advances in molecular testing have led to the discovery of several genes recurrently deregulated in familial HM including RUNX1, CEBPA, GATA2, ANKRD26, SRP72, PAX5, DDX41, ETV6, ATG2B/GSKIP and TERT/TERC. This review summarizes biological and clinical findings encountered within these disorders. Expert commentary: Identify and manage individuals with genetic predisposition is a current challenge for hematologists. Their identification has immediate implications for hematopoietic stem cell transplantation including donor selection and conditioning regimen. Importantly, several features, including familial and personal history as well as molecular and cytogenetic findings, may help clinicians to suspect an underlying genetic predisposition.

Heavy menstrual bleeding (HMB) is a common symptom in patients who present to the obstetrician-gynecologist or adolescent medicine specialist and might result from an underlying inherited bleeding disorder. Whereas relatively common bleeding disorders such as von Willebrand disease are often included in standard laboratory assessments, rarer platelet function disorders can be challenging to diagnose. Additionally, HMB can be a particularly difficult symptom to manage in adolescents with platelet function disorders, and it is associated with decreased quality of life. We review the diagnostic and management issues of patients with platelet function disorders through the presentation of 2 patient case reports, with a focus on a diagnosis of Glanzmann thrombasthenia, an inherited qualitative disorder that affects platelet function. Whereas the first patient presented to the emergency department before the diagnosis of a bleeding disorder and required a hematologic referral and extensive laboratory assessments, the second patient had been diagnosed with Glanzmann thrombasthenia as a child but experienced severe management challenges at the onset of menarche. In both patients, collaboration between the obstetrician-gynecologist or adolescent medicine specialist and the hematologist was critical for achieving acute management of the bleeding symptoms and for ensuring optimal long-term disease management. Together, these cases highlight the importance of properly identifying females with HMB who might have an undiagnosed bleeding disorder and of consulting with a hematologist to determine an appropriate management plan throughout all life stages., (Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Patients with concomitant cardiac and hematologic disorders presenting for noncardiac surgery are challenging. Anemic patients with cardiac disease should be approached in a methodical fashion. Transfusion triggers and target should be based on underlying symptomatology. The approach to anticoagulation management in patients with artificial heart valves, cardiac devices, or severe heart failure in the operative setting must encompass a complete understanding of the rationale of a patient's therapy as well as calculate the risk of changing this regimen. This article focuses common disorders and discusses strategies to optimize care in patients with coexisting cardiac and hematologic disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Inherited giant platelet disorders are a subgroup of congenital thrombocytopenias characterized by decreased platelet counts along with macroplatelets and variable bleeding symptoms. Harris platelet syndrome, a newly described rare entity, is a subtype of inherited giant platelet disorders and is characterized by mild-to-severe thrombocytopenia, macroplatelets, and no bleeding manifestations. This entity was observed incidentally in healthy blood donors from India in the early 2000s, and the reported cases to date have without exception originated from the same region of the Indian subcontinent. We herein report the occurrence of Harris platelet syndrome in patients from a different ethnogeographic origin.

Inherited macrothrombocytopenia is a subgroup of thrombocytopenias, and is characterised by the presence of giant platelets and decreased platelet count with variable bleeding manifestations. Bengal macrothrombocytopenia is a newly described entity, previously called asymptomatic constitutional macrothrombocytopenia (ACMT), presented with variable bleeding tendencies; with mild to severe thrombocytopenia and macro-platelets in their peripheral blood smear and it is not totally an innocuous condition as described previously., (Copyright © 2016 Elsevier Inc. All rights reserved.)